Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma

Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma(LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, butin roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing toepigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically byMAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation ofNRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppressionof GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility toapoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector foroncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs.